This blog is meant to allow Fragment-based Drug Design Practitioners to get together and discuss NON-CONFIDENTIAL issues regarding fragments.

30 July 2014

Fragments in the Caribbean

Last week saw the inaugural Zing FBDD conference in Punta
Cana, Dominican Republic. Zing has been around only since 2007, and seems to
focus on small conferences in exotic locales. The benefit is that they are able
to attract high-profile speakers, as illustrated by the group photo below.
However, in an era of shrinking travel budgets, getting approval to attend a
conference at a resort is becoming a bit more challenging. That said,
participants enjoyed nearly 30 presentations and great discussion – think of a
Gordon Conference without the dorms, and breaks on the beach.

My favorite “equation” from the conference comes from Mike
Serrano-Wu of the Broad Institute:

Undruggable = Undone

This was supported by some nice work on the anti-cancer
target MCL-1, which makes a protein-protein interaction that was widely consider undruggable just a few years
ago. An 19F NMR fragment screen gave
a hit-rate of around 10%, leading eventually to low nanomolar leads. Fragment optimization
was facilitated by a new crystal form of the protein that allowed the team to
rapidly generate over a dozen protein-ligand co-crystal structures. Rumor has
it that more details on this will be disclosed at FBLD 2014 in Basel in
September (there are still a few openings available, but register soon.)

MCL-1 also figured heavily in talks by Andrew Petros
(AbbVie, see also here) and Steve Fesik (Vanderbilt, see also here), who
described cell-permeable molecules with high picomolar activity in biochemical
assays. Steve also discussed programs against Ras and RPA, both also using SAR by NMR. As Mike Shapiro (Pfizer) pointed out in his opening presentation, one
of the breakthrough ideas of SAR by NMR was to screen a library more than once
per target, the second time in the presence of a first ligand to identify another. It is nice to see this strategy continuing to deliver against difficult
targets, though preliminary results of our current poll (right hand side of
page) indicate that linking is not necessarily easy.

One of the payoffs of doing fragment screens for many years
on dozens of targets is a rich internal dataset. Chris Murray (Astex) mentioned
that company researchers have solved close to 7000 protein crystal structures,
more than a third of them with fragment ligands. A cross-target analysis found
that hits tended to be more planar (ie, less “three-dimensional”, with
apologies to Pete Kenny) than non-hits. This was particularly true for kinases;
for six protein-protein interactions (PPIs) there was no correlation between
shape and hit rate. Although defining complexity is difficult, Chris provided
evidence that 3D fragments tend to be both larger and more complex.

Rod Hubbard (University of York and Vernalis) mentioned that
Vernalis has determined more than 4000 protein crystal structures. Since 2002,
2050 fragments have been screened against more than 30 targets. Based on
“sphericality” – the distance from the rod-sphere principle component axis –
hits against kinases are marginally less spherical, while PPI hits reflect the shape
of the overall library. So, despite the current push for more three-dimensional
fragments, it remains to be seen whether this will be useful.

Jonathan Mason (Heptares) described how successful fragment
approaches can be against membrane proteins such as GPCRs. Anyone who has
worked on these targets will know that the SAR can be razor sharp, and their
surfeit of structures is helping to explain this. For example, although many of
the protein-ligand interactions appear merely hydrophobic, some displace high-energy
water molecules, which can be revealed by crystal structures of both the free
and bound forms of the protein. Displacement of high energy water molecules
also helps to explain some “magic methyl” effects.

Fragment-finding methods were not neglected. Jonathan mentioned
that, for the A2A receptor, SPR identified only orthosteric ligands, while TINS
identified only allosteric ligands – the orthosteric ligands were actually too
potent to be detected by this technique. John Quinn (Takeda, formerly SensiQ)
and Aaron Martin (SensiQ) also discussed SPR, and in particular how variable
temperature SPR analyses could be used to rank ligands based on their enthalpic binding, though as Chris Murray warned, this information can be difficult to
use prospectively.

I also learned that a selective BCL-2 inhibitor from
Vernalis and Servier has just entered into Phase 1 clinical trials. This has
been the result of a long-running collaboration that has required creativity on
the part of the scientists and patience on the part of management.

There is much more to tell – for example Teddy's extended metaphor of the Silk Road (this one, not this one!) – but in the
interest of space I’ll stop here. Feel free to comment if you were there (or
even if you weren’t!)

A good example is RAS - people have been working on RAS for over 30 years (including fragment screens) and there's still nothing even remotely resembling a drug against this target and I'm willing to bet my pension (such that it is) that there won't be a drug targeting RAS on the market in my lifetime.